Pharmacokinetics, safety and bioequivalence of intravenous and oral formulations of the antiepileptic drug levetiracetam in healthy Chinesevolunteers
Lanlan Hu, Juan Zhou, Huan Zou, Yue Zhang, Jianlin Tang*
Base for Drug Clinical Trial, Xinqiao Hospital, the Third Military Medical University, Chongqing 400037, China
Abstract: The intravenous formulation of levetiracetam (LEV) has been available in clinical practice worldwide for several years, but not in China. In the present study, we aimed to evaluate the bioequivalence of intravenous and oral LEV (tablet), an antiepileptic drug, in healthy Chinese volunteers. Two randomized, single-dose (1500 mg), open-label, 2-period crossover trials were conducted as follows: study A, 15-min infusion; study B, 45-min infusion. A total of 22 healthy men participated in study A, and 24 healthy men and woman were enrolled in study B. In study A, blood samples were collected after termination of each treatment. In study B, samples were collected after oral or after the start of the intravenous administration. Safety and the ratio of intravenous/oral LEV for AUC0–t and Cmax were evaluated. The 90% confidence intervals of Cmax and AUC0–t ratios for LEV 1500-mg tablets versus 15-min intravenous administration were outside the bioequivalence limits (80.00%–125.00%). For LEV 45-min intravenous administration, bioequivalence versus 1500-mg tablets was within the range for Cmax and AUC0–t. The most frequently adverse event (AE) was somnolence. A total of eight subjects experienced nine mild AEs in study A, and 19 subjects experienced 29 mild AEs in study B. Intravenous infusions (15 and 45 min) of 1500-mg LEV were as well tolerated as the oral tablet. Bioequivalence was demonstrated by 45-min infusions. Therefore, direct conversion from oral to intravenous LEV 1500 mg (45-min infusion), or vice versa, was possible.
Keywords: Levetiracetam; Epilepsy; Intravenous formulation; Bioequivalence; Safety and tolerability
CLC number: R969.1 Document code: A Article ID: 1003–1057(2018)11–777–10
Levetiracetam (LEV) is a broad-spectrum antiepileptic drug (AED) that binds to synaptic vesicle protein 2Awith different pharmacological targets from other classic AEDs[1,2]. Oral LEV has a good safety and pharmacokinetic(PK) profile with complete absorption, decreased plasma protein binding, non-cytochrome P450 dependentmetabolism and minimal drug interactions[3–7]. Both adults and children show good tolerability of LEV since it was approved in China in 2007 as oral tablet formulation[8,9]. Because of its favorable properties, an intravenous formulation of LEV has been developed as an alternative for some patients whose oral medication is temporarily not feasible (e.g., upper gastrointestinalintolerance or malabsorption, patients with status epilepticus and acute repetitive seizures)[10–15].
Although intravenous formulation of LEV has been available in clinical practice worldwide, it is not applied in China. Limited information exists on the PK properties or tolerability of intravenous LEV in Chinese population. In 2006, bioequivalence between oral LEV and the intravenous formulation was demonstrated in 18 healthy Caucasian adult volunteers. In this study, 1500 mg of LEV is diluted in 100 mL of sterile saline solution (0.9%) and infused over 15 min. It is demonstrated that LEV intravenous infusion is equivalent to 3×500 mgoral tablets. Additionally, a bioequivalent trial has been developed in Japanese healthy male and femalevolunteers in 2014. The design is similar to thatof the bioequivalence study previously conductedin Caucasian adults. The results show that a 15-minintravenous infusion of LEV (1500 mg) and oral tablets (three 500-mg oral tablets) are not bioequivalentsince the Cmax is higher after intravenous administration compared with oral dosing . Recently, an open-label bioequivalence of intravenous infusion of LEV 1500 mg (over 45 min) and oral LEV 1500 mg tablets has been established in healthy Chinese subjects. The result of study shows that intravenous LEV 45-min infusion is bioequivalent to oral tablets. The 90% confidence interval (CI) of Cmax is 100.5%–128.6% from this article. Although it fits the range of 70%–143%, it exceeds the upper limit of 80.00%–125.00% specified by China Food andDrug Administration (CFDA) in 2015. We obtained the same result in Japanese in our first phase of the trial. Because of the comparison between two different dosage forms (intravenous vs. oral), the time of intravenous infusion could affect the Cmax of the drug, possibly making the results of bioequivalencestudies misleading.
The primary objective of the trials presented here was to evaluate the bioequivalence, safety, and tolerability of 15- and 45-min intravenous infusions of 1500-mg LEV and the 1500-mg oral tablet (reference) in healthy Chinese participants. The secondary objective was to assess the impact of intravenous infusion time and sampling schedule on bioequivalence between LEV intravenous infusion and oral tablet. This would be required in patients converting between oral and intravenous formulations.
2. Materials and methods
2.1. Study design and population
In the present study, two randomized, single-dose (1500 mg), open-label, 2-period crossover trials were conducted in healthy Chinese volunteers as follows: study A, 15-min infusion and oral tablet; study B, 45-min infusion and oral tablet. These two clinical studies were performed in accordance with the principles of the Declaration of Helsinki and its amendments, and approved by the Ethics Committee of Second AffiliatedHospital of Third Military Medical University in Chongqing, China.
In both trials, volunteers were randomized to receive oral or intravenous LEV first. After the first treatment period, a washout period of at least 7 d was allowed before the next treatment started. All subjects were hospitalized on day 1of each treatment period, and single doses of trial medication were administered on the morning of day 1. Subjects remained in a supine position while receiving the intravenous infusion, and in a sitting position when receiving tablets with 240 mL of water. They were fasted for 10 h prior to each experiment. Water intake was not allowed for 1 h either before or after administration, and food intake was not allowed for at least 4.0 h after administration. Smoking, alcohol or beverages (e.g. coffee, tea, and cola) were not allowed during the study.
Only men were recruited for bioequivalence studies in study A. In study B, male and female volunteerswere recruited. They were considered eligible for the study when they met all of the following inclusion criteria. Healthy Chinese males and females, 18–40 years of age, of normal body weight (body mass index,BMI 18–25) were enrolled in the trials after providing written informed consent. Eligible participants had no significant hepatic, renal, gastrointestinal or hematologic diseases, as examined by medical history, physical examination, ECG and clinical laboratory tests (ie, hematology, blood biochemistry, urinalysis, hepatic and renal function). Subjects were excluded if they had a history of allergic reactions to food or drugs or if they received any drug (including over-the-counter remedies and herbal products) within 2 weeks before the study. Anyone who participated in clinical trials within 3 months before the test or who had a history of drug or alcohol abuse were also excluded.
2.2. Study medication
In both trials, LEV was administered at a dose of 1500 mg, the oral dose consisted of three 500-mg tablets, and the intravenous dose, delivered via light-resistant infusion set with precise filter, was provided as a 15-mL solution (500 mg/5 mL) diluted with 100 mL of 0.9% sterile saline. The infusion duration was 15 min in study A and 45 min in study B.
2.3. Sample collection and analytical methods
Plasma samples (4 mL for study A and 3 mL for study B) were collected by placing an indwelling catheterin the forearm vein or by immediate venipuncture. In study A, blood samples were collected at pre-dose, 2, 5, 10, 15, 30 min and 1, 2, 3, 6, 9, 12, 24, 36 h after termination of each treatment. In study B, blood samples were collected at pre-dose, 10, 20, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 36, 48 h after oral dose administration or after the start of the intravenous infusion. Blood samples were drawn into pre-labeled anticoagulant tubes. The plasma was separated by centrifugation at 3000 r/min for 10 min at room temperature. Plasma was frozen at –80 ºC in labeled centrifuge tubes until analysis.
In both studies, LEV plasma concentrations were determined using similar validated UPLC-MS/MS. Both methods used 3-amino-2-naphthoic acid (purity 97.0%, Tokyo Chemical Industry Co., Ltd.) as the internal standard (IS), and sample clean-up procedures were conducted by acetonitrileprecipitation. The calibration range was 0.5–128 and 0.5–120 µg/mL with lower limits of quantification of 0.5 and 0.5 µg/mL in studies A and B, respectively. Quality control samples were analyzed at concentration levels: 0.5, 1.0, 26.0, 51.0 and 102.0 µg/mL (study A) and at 0.5, 1.5, 5.0, 9.0, 15.0, 50.0 and 90.0 µg/mL (study B). In both studies, the mean precisions of quality control samples were <11%, and mean inaccuracies <13% were found, indicating that reliable concentration data were obtained in both studies.
2.4. PK analyses
The primary PK parameters of LEV were Cmax, AUC0–t and AUC0–∞, and the ratio of intravenous LEV treatment/oral LEV treatment of these parameters to determine bioequivalence.
Secondary PK parameters of interest included time to reach Cmax (tmax ) and terminal half-life (t1/2). PK parameters were determined using non-compartmental methods.
2.5. Safety evaluation
Information on adverse events (AEs) was collected from the time of administrating drug to 2 weeks after the last dose. Physical examination, abnormal ECGs and laboratory tests were repeated on the subjects at the end of the study.
In these two studies, tolerability was monitored by hospital staff during the study using AE collection by direct observation, spontaneous reports, and nonspecific questioning. Any undesirable sign or medical condition occurring after the start of the study was recorded regardless of the suspected relation to the study drug. AEs were graded as mild, moderate or severe.
Safety was assessed by monitoring vital signs (body temperature, heart rate, sitting blood pressure [BP]), abnormal ECGs and laboratory tests (i.e. hematology, urinalysis, hepatic and renal functions) at baseline and at completion of the study. Systolic and diastolic BPs as well as heart rate were measured using an automatic sphygmomanometer (model HEM-7209, OMRON Dalian Co., Ltd., Dalian, China) after the volunteers were seated quietly for ≥10 min, with the arm supported at heart level. Laboratory tests were performed in the laboratory of Xinqiao Hospital.
2.6. Statistical analysis
Log-transformed data of AUC0–t, AUC0–∞and Cmax were analyzed for each treatment using analysis of variance (ANOVA). Based on these analyses, point estimates and 90% CIs for the ratios of 15- and 45-min infusion versus tablet were calculated for AUC0–t, AUC0–∞and Cmax. Bioequivalence would be concluded if the 90% CIs for the treatment ratios were fully contained within the 80.00%–125.00% acceptance range for AUC0–t, AUC0–∞and Cmax. Parameter tmax was evaluated by method of descriptive statistics. All statistical calculations were performed using DAS 3.3.0 software (Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China).
3.1. Baseline demographics
In study A, a total of 26 volunteers were judged according to inclusion/exclusion criteria. Twenty-two of them were enrolled, and 21 completed the study. One subject (taking the reference drug) withdrew consent for personal reasons before the second period (we contacted this volunteer by telephone and verified the withdrawal was not due to AEs). Another subject was excluded because only even number can be calculated by the statistical software. Therefore, only 20 subjects were finally included in the statistical analysis. In study B, a total of 33 volunteers were judged according to inclusion/exclusion criteria. Twenty-four of them were enrolled. All of the subjects completed the study and PK analysis. Baseline demographic characteristics were shown in Table 1.
Table 1. Baseline Demographics characteristics of volunteers in studies A and B.
SS, safety set; PKS, pharmacokinetic set. Data are means±SD, with ranges in parentheses.
3.2. PK analysisand bioequivalence evaluation
3.2.1. Study A: intravenous (15 min) vs. oral administrationin Chinese volunteers
In study A, the mean plasma concentration-time curves after a single dose of 1500 mg administered either as a 15-min intravenous infusion (test) or as oral tablets (reference) were shown in Figure 1. Plasma concentration-time profiles differed between the intravenous infusion and oral tablets during the first 6 h after administration. PK parameters followingintravenous and oral administration of LEV were presented in Table 2. Mean (SD) values of LEV for the test and reference products were: Cmax, 72.02 (11.69) and 59.86 (11.21) μg/mL, respectively; tmax, 0.05 (0.03) and 1.20 (0.66) h; t1/2, 8.20 (1.35) and 7.44 (1.09) h; AUC0–36, 445.44 (123.62) and 495.72 (104.54) μg/mL/h; and AUC0–∞, 462.88 (127.76) and 510.59 (110.44) μg/mL/h. Mean Cmax was higher, and tmax was achieved earlier after intravenous dosing than after oral administration. Elimination phases were substantially parallel for intravenous infusion and oral administration.
Figure 1. Mean±SD LEV plasma concentrations followed a 15-min infusion or oral tablet administration of 1500-mg LEV in healthy Chinese volunteers up to 36 h after LEV administration. IV=Intravenous.
Table 2. Single-dose PK parameters after intravenous infusion or oral administration of 1500-mg LEV (PK dataset).
Data are expressed as geometric mean (% CV) unless otherwise specified.
The 90% CI of the ratio (test/reference) of intravenous to oral administration for the log-transformed values of Cmax, AUC0–36, and AUC0–∞for LEV are listed in Table 3.The calculated 90% CIs of the geometric mean test/reference ratio ranged from 111.77 to 130.52 for Cmax, from 77.95 to 99.82for AUC0–36 and from 79.12 to 100.41 for AUC0–∞. The 90% CI did not meet the acceptance range for bioequivalence between AUC and Cmax.
Table 3. Bioequivalence of oral and intravenous infusion LEV: ANOVA.
3.2.2. Study B: intravenous (45 min) vs. oral administrationin Chinese volunteers
In study B, the mean LEV plasma concentration-time profiles after a single dose of 1500 mg administered either as a 45-min intravenous infusion (test) or as oral tablets (reference) suggested that the test formulation had similar bioavailability to the reference formulation (Fig. 2). PK parameters following intravenous and oral administration of LEV were presented in Table 2. Mean (SD) values of LEV for the test and referenceproducts were: Cmax, 47.65 (13.82) and 44.10 (13.38) μg/mL, respectively; tmax, 0.76 (0.12) and 1.25 (1.02) h; t1/2, 7.33 (1.13) and 7.28 (1.23) h; AUC0–48, 424.44 (83.76) and 422.81 (70.89) μg/mL/h; andAUC0–∞, 433.13 (85.74) and 431.37 (72.17) μg/mL/h. Cmax was achieved at the end of the infusion (45 min) for single dose. The mean (SD) Cmax after the intravenous infusion was similar to that after oral dosing. Mean values for AUC0–t and AUC0–∞ were similar for both LEV formulations, indicating that the oral tablet had a 100% absolute bioavailability.
Figure 2. Mean±SD LEV plasma concentrations following a 45-min infusion or oral tablet administration of 1500-mg LEV in healthy Chinese volunteers up to 48 h after LEV administration. IV = Intravenous.
The 90% CIs of the ratio (test/reference) of intravenous to oral administration for the log-transformed values of Cmax, AUC0–48, and AUC0–∞ for LEV were listed in Table 3. The calculated 90% CI of the geometric mean test/reference ratio ranged from 100.43 to 117.20 for Cmax, from 97.30 to 102.96 for AUC0–48and from 97.25 to 103.02 for AUC0–∞. The 90 % CIs were fully included within the acceptance range for bioequivalence between AUC and Cmax.
3.3. Safety evaluation
In this population of healthy Chinese subjects, no serious or unexpected AEs occurred in these two studies. During study A, eight subjects experienced nine mild AEs; four were reported following the 15-min infusion and five following the oral treatment. The most commonly reported AEs in both treatment groups were dizziness and somnolence. In study B, 19 volunteers reported 29 AEs: 19 reported following the 45-min infusion and 10 following the oral LEV treatment. The most frequently AEs for treatment groups were dizziness and somnolence. These were considered possibly to be related to trial medication by the investigator. None of the volunteers discontinued the study due to AEs.
No injection site reactions were observed after intravenous LEV infusion in either study. Administration of LEV, whether intravenous or oral, did not have a clinically relevant influence on vital signs, ECG or safety laboratory parameters.
Although LEV is usually administered orally, some patients may be unable to swallow oral tablets and have a temporary need for intravenous administration. The two studies described here evaluated the bioequivalenceof 1500-mg LEV administered intravenously over 15 min (study A) or 45 min (study B) with the oral LEV tablet in healthy Chinese volunteers. The PK parameters measured during the studies were also used to assess the bioavailability of the oral LEV tablet compared with the intravenous LEV formulation.
Bioequivalence in these studies was defined according to guidance provided by the CFDA, whereby the oral tablet and intravenous infusions of LEV would be considered bioequivalent if the 90% CIs for the ratio of the test and reference products were contained within the acceptance interval of 80.00%–125.00% for the PK parameters Cmax, AUC0–t, and AUC0–∞.
In most cases, the ratios for Cmax, AUC0–t, and AUC0–∞of intravenous and oral LEV tablets were approximately 1; the higher Cmax ratio of the 15-min intravenous LEV treatment groups was attributed to shorter infusion durations. In study A, the observed 90% CIs for the Cmax, AUC0–t, and AUC0–∞ ratio of the 15-min infusion to the oral tablet exceeded the limit of the accepted bioequivalence range of 80.00%–125.00%, and therefore,could not be considered bioequivalent to the oral tablet. LEV plasma concentration-time curves differed between intravenous and oral administration during the first 6 h after dosing. The first sampling point was collected after termination of each treatment period. Therefore, tmax was achieved at the end of the infusion period (about the first sampling point, 3 min), but occurred later after oral treatment (about 1.2 h). Cmaxafter intravenous was transient and was followed by a rapid decrease in plasma concentration. For most volunteers (14/20, 70%), Cmax was higher after intravenousinfusion than after oral administration. The rate ofabsorption of LEV tended to be lower after oral administration than after intravenous administration, as evidenced by lower Cmax and prolonged tmax values of oral administration. The AUC0–t was not significantly different after intravenous infusion (445.44 [123.62] μg/mL/h) and after oral administration (495.72 [104.54] μg/mL/h). These ?ndings were consistent with those of the study conducted in the Japanese volunteers. The design of this study is similar to ours, but it has a slight differencein sampling schedule (i.e., there is an additional sampling point at 45 min post-dose and the first sample point is collected after the start of the infusion).In contrast to these findings, a previous study of similar design in other race (i.e., Caucasian volunteers) has described that single doses of LEV 1500 mg delivered as a 15-min intravenous infusion and as oral tablets are bioequivalent with respect to both Cmax and AUC. The differences in sampling schedule and the racial differences might explain the varying results. Additionally, the result of ANOVA statistical analysis showed that there was a significant difference between the periods (P<0.05, data not shown) in study A. The influences of drug residue and instrument determination on results were investigated and excluded. Therefore, further study needs to validate other factors, such as effects of food or physiologic factors of the participants.
The different routes of administration, the LEV intravenous injection (test) and oral tablets (reference), led to different rate and extent of absorption in the same subject. Intravenous administration is the fastest way to deliver fluids and medications throughout the body, while oral medication needs to go through the human digestive system before passing into the bloodstream. The speed and time of intravenousinfusion directly affect its tmax and Cmax in human plasma and then affect AUC. Based on different routes of treatment (intravenous and oral), it is very important to achieve similar plasma concentration by designing appropriate administration time. Therefore, we adjustedthe intravenous infusion time (i.e., 45 min) andsampling schedule (i.e., an additional sampling point at 45 min post dose, and the first sample point was collected after the start of the intravenous infusion) in study B, and found that a single 1500-mg dose of LEV administered as a 45-min intravenous infusion was bioequivalent to the same dose given as oral tablets. The ratios of the 45-min infusion to oral tabletadministration for AUC0–t, AUC0–∞ and Cmax were all close to 1, or a point estimate of 100. The 90% CI was fully included within the acceptance range for AUC and Cmax. As expected, Cmax was achieved at the end of the infusion (about45 min) when the intravenous route was adopted. In the previous bioequivalence study conducted in Caucasian and Japanese volunteers[16,17], tmax occurs after the end of the infusion (about 15 min). There were no significant differences in parameters determined from the oral and intravenous routes. Similar values for AUC0–t, AUC0–∞ were measuredfor intravenous LEV infusions and the oral tablet, confirming the approximate 100% bioavailability of the oral tablet observed in earlier trials[20,21].
For tolerability, the incidence of AEs after dosing of intravenous formulation was higher than oral tablet. Consistent with the reported safety profile of oral LEV[2,22], the most common AEs with intravenous LEV in this study were dizziness and somnolence. No clinically relevant changes from baseline in clinical chemistry parameters, vital signs, physical examination findings or ECG parameters were observed in either study with LEV treatment. Overall, evaluation of the safety data showed that 1500 mg intravenous LEV infusions of 15- and 45-min duration were well tolerated and had similar safety profiles to the oral 1500-mg LEV tablet.
Bioequivalence of intravenous infusion of LEV1500 mg (15- and 45-min) and oral LEV 1500 mg tablets was established in healthy Chinese subjects. Across both studies, single dose intravenous administration or oral LEV tablets (1500 mg) were well tolerated. In study A, intravenous LEV 15-min infusion was not bioequivalent to oral tablets based on the differences of Cmax and AUC. The subsequent study B showed that PK profiles were similar after 45-min intravenousinfusion by adjusting the sampling schedule. Therefore,direct conversion from oral to intravenous LEV administration(45-min infusion), or vice versa, is possible. This research may help marketing this new intravenous formulation in China.
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胡岚岚, 周娟, 邹欢, 张玥, 汤建林*
第三军医大学新桥医院 临床药理基地, 重庆 400037
摘要: 左乙拉西坦(LEV)的静脉注射制剂在世界范围内的临床应用已有多年, 但在中国还没有上市。在本研究中, 我们旨在评估静脉和口服的抗癫痫药物左乙拉西坦在中国健康志愿者中的生物等效性。两个随机、单剂量(1500毫克)、开放、双周期、交叉试验按照如下方式进行: A试验: 入选健康男性受试者22例, 静脉滴注15分钟, 于口服给药和静脉滴注结束后进行血样的采集; B试验: 入选健康男性和女性受试者24例, 静脉滴注45分钟, 于口服给药和静脉滴注开始后进行血样的采集。最后对左乙拉西坦静脉注射和口服两种制剂的AUC0-t(从0到最后可测血浆浓度的曲线下面积)、Cmax(最大血浆浓度)的几何均值比及安全性进行评价。结果显示, 左乙拉西坦(1500mg)静脉滴注15分钟与口服片剂相比, AUC0-t和Cmax的90%置信区间未在80.00%～125.00%的接受范围之内, 而静脉滴注45分钟的AUC0-t和Cmax与口服片剂相比显示等效。两次试验最常见的不良反应是嗜睡, 在试验A中共有8例受试者发生了9次轻度不良反应, 在试验B中共有19例受试者发生29次轻度不良反应。由于45分钟的静脉滴注试验证实了片剂和注射液的生物等效性, 所以左乙拉西坦1500 mg的静脉注射制剂(45分钟滴注)和口服制剂具有可替换性。
关键词: 左乙拉西坦; 癫痫; 静脉注射剂型; 生物等效性; 安全性和耐受性